This invention relates to new guanidine derivatives.
One object of this invention is to provide the new and useful guanidine derivatives and salts thereof which possess a strong inhibitory activity on Na+/H+ exchange in cells.
Another object of this invention is to provide processes for preparation of the guanidine derivatives and salts thereof.
A further object of this invention is to provide a pharmaceutical composition comprising said guanidine derivatives or a pharmaceutically acceptable salt thereof.
Still further object of this invention is to provide a use of said guanidine derivatives or a pharmaceutically acceptable salt thereof as a medicament for the treatment and/or prevention of cardiovascular diseases, cerebrovascular diseases, renal diseases, arteriosclerosis, shock and the like in human being and animals.
Some guanidine derivatives having pharmaceutical activities such as inhibitory activity on Na+/H+ exchange in cells have been known as described in WO 98/55475.
The object guanidine derivatives of the present invention are novel and can be represented by the following general formula (I): 
wherein
R1 is hydrogen or halogen,
R2 is hydroxy, acyl(lower)alkoxy, hydroxy(lower)alkyl, lower alkoxy(lower)alkyl, lower alkylthio(lower)alkyl, mono(or di or tri)halo(lower)alkyl, (ethoxycarbonyl)amino, sulfamoylamino, (dimethylsulfamoyl)amino, N,N-di(lower)alkylamino(lower)alkyl, hydroxyimino(lower)alkyl, lower alkoxyimino(lower)alkyl, acyl, lower alkylthio, cyano, acyl(lower)alkyl, acyl(lower)alkenyl, aryl which has one or more substituent(s) or a heterocyclic group which has one or more substituent(s), and
X is xe2x80x94CH2xe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94Oxe2x80x94 or xe2x80x94NHxe2x80x94.
The object compound (I) of the present invention can be prepared by the following process.
Process (1) 
wherein R1, R2 and X are each as defined above.
The starting compound (II) can be prepared by the following processes or Preparations mentioned below, or similar manners thereto.
Process (A) 
wherein
R1 and R2 are each as defined above,
R3 is lower alkyl, and
R4 is lower alkyl.
Salts of the object guanidine derivatives (I) are pharmaceutically acceptable, conventional non-toxic salts and may include a salt with a base or an acid addition salt such as a salt with an inorganic base, for example, an alkali metal salt (e.g., sodium salt, potassium salt, etc.), an alkaline earth metal salt (e.g., calcium salt, magnesium salt, etc.), an ammonium salt; a salt with an organic base, for example, an organic amine salt (e.g., triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,Nxe2x80x2-dibenzylethylenediamine salt, etc.); an inorganic acid addition salt (e.g., hydrochloride, hydrobromide, sulfate, phosphate, etc.); an organic carboxylic or sulfonic acid addition salt (e.g., formate, acetate, trifluoroacetate, maleate, tartrate, citrate, fumarate, isethionate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.); a salt with a basic or acidic amino acid (e.g., arginine, aspartic acid, glutamic acid, etc.).
In the above and subsequent descriptions of the present specification, suitable examples and illustration of the various definitions which the present invention intends to include within the scope thereof are explained in detail as follows.
The term xe2x80x9clowerxe2x80x9d is used to intend a group having 1 to 6, preferably 1 to 4, carbon atom(s), unless otherwise provided.
Suitable xe2x80x9clower alkylxe2x80x9d and xe2x80x9clower alkylxe2x80x9d moiety in the terms xe2x80x9chydroxy(lower)alkylxe2x80x9d, xe2x80x9chydroxyimino(lower)alkylxe2x80x9d, xe2x80x9clower alkylthioxe2x80x9d, etc. may include straight or branched one having 1 to 6 carbon atom(s), such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, tert-pentyl, hexyl, and the like, preferably one having 1 to 4 carbon atom(s).
Suitable xe2x80x9clower alkenylxe2x80x9d and xe2x80x9clower alkenylxe2x80x9d moiety in the term xe2x80x9cacyl(lower)alkenylxe2x80x9d may include vinyl, 1-(or 2-)propenyl, 1-(or 2- or 3-)butenyl, 1-(or 2- or 3- or 4-)pentenyl, 1-(or 2- or 3- or 4- or 5-)hexenyl, methylvinyl, ethylvinyl, 1-(or 2- or 3-)methyl-1-(or 2-)propenyl, 1-(or 2- or 3-)ethyl-1-(or 2-)propenyl, 1-(or 2- or 3- or 4-)methyl-1-(or 2- or 3-)butenyl, and the like, in which more preferable example may be C2-C4 alkenyl.
Suitable xe2x80x9clower alkoxyxe2x80x9d and xe2x80x9clower alkoxyxe2x80x9d moiety in the terms xe2x80x9cacyl(lower)alkoxyxe2x80x9d, xe2x80x9clower alkoxy(lower)alkylxe2x80x9d and xe2x80x9clower alkoxyimino(lower)alkylxe2x80x9d may include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, pentyloxy, t-pentyloxy, hexyloxy and the like, in which the preferred one may be C1-C4 alkoxy.
Suitable xe2x80x9chalogenxe2x80x9d may include fluorine, bromine, chlorine and iodine.
Mono(or di or tri)halo(lower)alkyl may include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, bromomethyl, dibromomethyl, tribromomethyl, 1 or 2-fluoroethyl, 1 or 2-bromoethyl, 1 or 2-chloroethyl, 1,1-difluoroethyl, 2,2-difluoroethyl and the like, in which the preferred one is trifluoromethyl.
Suitable xe2x80x9carylxe2x80x9d may include phenyl, naphthyl and the like.
Suitable xe2x80x9cacylxe2x80x9d and xe2x80x9cacylxe2x80x9d moiety in the terms xe2x80x9cacyl(lower)alkoxyxe2x80x9d, xe2x80x9cacylaminoxe2x80x9d and xe2x80x9cacyl(lower)alkenylxe2x80x9d may include carboxy, carbamoyl, aliphatic acyl group and acyl group containing an aromatic ring, which is referred to as aromatic acyl, or heterocyclic ring, which is referred to as heterocyclic acyl.
Suitable example of said acyl may be illustrated as follows:
Carboxy; Carbamoyl; Thiocarbamoyl; Sulfamoyl;
Aliphatic acyl such as lower or higher alkanoyl (e.g., formyl, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 2,2-dimethylpropanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, heptadecanoyl, octadecanoyl, nonadecanoyl, icosanoyl, etc.);
lower or higher alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, t-pentyloxycarbonyl, heptyloxycarbonyl, etc.);
lower or higher alkylsulfonyl (e.g., methylsulfonyl, ethylsulfonyl, etc.);
lower or higher alkylsulfinyl (e.g., methylsulfinyl, ethylsulfinyl, etc.);
lower or higher alkoxysulfonyl (e.g., methoxysulfonyl, ethoxysulfonyl, etc.);
lower or higher alkoxysulfinyl (e.g., methoxysulfinyl, ethoxysulfinyl, etc.);
mono(or di or tri)halo(lower)alkylsulfonyl [e.g. fluoromethylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonyl, chloromethylsulfonyl, dichloromethylsulfonyl, trichloromethylsulfonyl, 1 or 2-fluoroethylsulfonyl, 1 or 2-chloroethylsulfonyl, etc.);
mono(or di or tri)halo(lower)alkylsulfinyl [e.g. fluoromethylsulfinyl, difluoromethylsulfinyl, trifluoromethylsulfinyl, chloromethylsulfinyl, dichloromethylsulfinyl, trichloromethylsulfinyl, 1 or 2-fluoroethylsulfinyl, 1 or 2-chloroethylsulfinyl, etc.); or the like;
Aromatic acyl such as
aroyl (e.g., benzoyl, toluoyl, naphthoyl, etc.);
ar(lower)alkanoyl [e.g., phenyl(lower)alkanoyl (e.g., phenylacetyl, phenylpropanoyl, phenylbutanoyl, phenylisobutanoyl, phenylpentanoyl, phenylhexanoyl, etc.), naphthyl(lower)alkanoyl (e.g., naphthylacetyl, naphthylpropanoyl, naphthylbutanoyl, etc.), etc.]; ar(lower)alkenoyl [e.g., phenyl(lower)alkenoyl (e.g., phenylpropenoyl, phenylbutenoyl, phenylmethacryloyl, phenylpentenoyl, phenylhexenoyl, etc.), naphthyl(lower)alkenoyl (e.g., naphthylpropenoyl, naphthylbutenoyl, etc.), etc.];
ar(lower)alkoxycarbonyl [e.g., phenyl(lower)alkoxycarbonyl (e.g., benzyloxycarbonyl, etc.), etc.];
aryloxycarbonyl (e.g., phenoxycarbonyl, naphthyloxycarbonyl, etc.);
aryloxy(lower)alkanoyl (e.g., phenoxyacetyl, phenoxypropionyl, etc.);
arylglyoxyloyl (e.g., phenylglyoxyloyl, naphthylglyoxyloyl, etc.);
arylsulfonyl (e.g., phenylsulfonyl, p-tolylsulfonyl, etc.);
arylsulfinyl (e.g., phenylsulfinyl, p-tolylsulfinyl, etc.); or the like;
Heterocyclic acyl such as
heterocycliccarbonyl;
heterocyclicsulfonyl;
heterocyclic(lower)alkanoyl (e.g., heterocyclicacetyl, heterocyclicpropanoyl, heterocyclicbutanoyl, heterocyclicpentanoyl, heterocyclichexanoyl, etc.);
heterocyclic(lower)alkenoyl (e.g., heterocyclicpropenoyl, heterocyclicbutenoyl, heterocyclicpentenoyl, heterocyclichexenoyl, etc.); heterocyclicglyoxyloyl; or the like.
Suitable xe2x80x9cheterocyclicxe2x80x9d and xe2x80x9cheterocyclicxe2x80x9d moiety in the terms xe2x80x9cheterocycliccarbonylxe2x80x9d, xe2x80x9cheterocyclic(lower)alkanoylxe2x80x9d, heterocyclic(lower)alkenoylxe2x80x9d, xe2x80x9cheterocyclicglyoxyloylxe2x80x9d, etc. may include saturated or unsaturated, monocyclic or polycyclic heterocyclic group containing at least one hetero-atom such as an oxygen, sulfur, nitrogen atom and the like.
And, especially preferable heterocyclic group may be heterocyclic group such as
unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, dihydropyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl (e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.), tetrazolyl (e.g., 1H-tetrazolyl, 2H-tetrazolyl, etc.), etc.;
saturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, pyrrolidinyl, imidazolidinyl, piperidyl, piperazinyl, etc.;
unsaturated condensed heterocyclic group containing 1 to 4 nitrogen atom(s), for example, indolyl, isoindolyl, indolinyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, etc.;
unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, oxazolyl, isoxazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.), etc.;
saturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, oxazolidinyl, morpholinyl, sydnonyl, etc.;
unsaturated condensed heterocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, benzoxazolyl, benzoxadiazolyl, etc.;
unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, thiazolyl, isothiazolyl, thiadiazolyl (e.g., 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.), dihydrothiazinyl, etc.;
saturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, thiazolidinyl, etc.;
unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 to 2 sulfur atom(s), for example, thienyl, dihydrodithiinyl, dihydrodithionyl, etc.;
unsaturated condensed heterocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, benzothiazolyl, benzothiadiazolyl, etc.;
unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing an oxygen atom, for example, furyl, etc.;
unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing an oxygen atom and 1 to 2 sulfur atom(s), for example, dihydrooxathiinyl, etc.;
unsaturated condensed heterocyclic group containing 1 to 2 sulfur atom(s), for example, benzothienyl, benzodithiinyl, etc.;
unsaturated condensed heterocyclic group containing an oxygen atom and 1 to 2 sulfur atom(s), for example, benzoxathiinyl, etc.; and the like.
The acyl moiety as stated above may have 1 to 10 (preferably 1 to 4), same or different, suitable substituent(s) such as lower alkyl as exemplified above; lower alkoxy as exemplified above; lower alkylthio wherein lower alkyl moiety is as exemplified above; lower alkylamino wherein lower alkyl moiety is as exemplified above; halogen; amino; protected amino (e.g., acylamino, benzylamino, tritylamino, etc.); guanidino; hydroxy; cyano; nitro; carboxy; sulfo; sulfamoyl; imino; oxo; amino(lower)alkyl wherein lower alkyl moiety is as exemplified above; carbamoyloxy; hydroxy(lower)alkyl wherein lower alkyl moiety is as exemplified above; diamino(lower)alkylidene (e.g., diaminomethylene, etc.); di(lower)alkylamino wherein lower alkyl moiety is as exemplified above; di(lower)alkylamino(lower)alkyl wherein lower alkyl moiety is as exemplified above, or the like.
Suitable xe2x80x9csubstituentxe2x80x9d in the terms xe2x80x9caryl which may have one or more substituent(s)xe2x80x9d, wherein the preferable number of substituent(s) is 1 to 4, and the more preferable one is 1 or 2, and xe2x80x9ca heterocyclic group which may have one or more substituent(s)xe2x80x9d, wherein the preferable number of substituent(s) is 1 to 4, and the more preferable one is 1 or 2, may include lower alkyl, lower alkoxy, lower alkenyl, lower alkynyl (e.g., ethynyl, 1-propynyl, propargyl, 1-methylpropargyl, 1-methylpropargyl, 1 or 2 or 3-butynyl, 1 or 2 or 3 or 4-pentynyl, 1 or 2 or 3 or 4 or 5-hexynyl, etc.), mono(or di or tri)halo(lower)alkyl (e.g., fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, bromomethyl, dibromomethyl, tribromomethyl, 1 or 2-fluoroethyl, 1 or 2-bromoethyl, 1 or 2-chloroethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, etc.), halogen, carboxy, hydroxy, aryl, ar(lower)alkyl such as phenyl(lower)alkyl (e.g., benzyl, phenethyl, phenylpropyl, etc.), carboxy(lower)alkyl, nitro, amino, di(lower)alkylamino (e.g., dimethylamino, diethylamino, diisopropylamino, ethylmethylamino, isopropylmethylamino, ethylmethylamino, ethylpropylamino, etc.), hydroxy(lower)alkyl, acyl, cyano, mercapto, lower alkylthio (e.g., methylthio, ethylthio, propylthio, isopropylthio, butylthio, etc.), imino, oxo, and the like.
The process for preparing the object compound and the starting compound of the present invention is explained in detail in the following.
Process (1)
The compound (I) or a salt thereof can be prepared by reacting the compound (II) or its reactive derivative at the carboxy group, or a salt thereof with the compound (III) or its reactive derivative at the imino group, or a salt thereof.
Suitable reactive derivative at the imino group of the compound (III) may include a silyl derivative formed by the reaction of the compound (III) with a silyl compound such as bis(trimethylsilyl)acetamide, mono(trimethylsilyl)acetamide [e.g. N-(trimethylsilyl)acetamide], bis(trimethylsilyl)urea or the like; a derivative formed by reaction of the compound (III) with phosphorus trichloride or phosgene, and the like.
Suitable salts of the compound (II) and its reactive derivative can be referred to the ones as exemplified for the compound (I).
Suitable reactive derivative at the carboxy group of the compound (II) may include a conventional one such as an acid halide, an acid anhydride, an activated amide, an activated ester, and the like.
Suitable examples of the reactive derivatives may be an acid chloride; an acid azide; a mixed acid anhydride with an acid such as substituted phosphoric acid [e.g. dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid halogenated phosphoric acid, etc.], dialkylphosphorous acid, sulfurous acid, thiosulfuric acid, sulfuric acid, sulfonic acid [e.g. methanesulfonic acid, etc.], aliphatic carboxylic acid [e.g. acetic acid, propionic acid, butyric acid, isobutyric acid, pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyric acid, trichloroacetic acid, etc.] or aromatic carboxylic acid [e.g. benzoic acid, etc.]; a symmetrical acid anhydride; an activated amide with imidazole, 1-hydroxy-1H-benzotriazole, 4-substituted imidazole, dimethylpyrazole, triazole or tetrazole; or an activated ester [e.g. cyanomethyl ester, methyl ester, ethyl ester, methoxymethyl ester, dimethyliminomethyl 
ester, vinyl ester, propargyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester, phenylazophenyl ester, phenyl thioester, p-nitrophenyl thioester, p-cresyl thioester, benzothiazolyl thioester, carboxymethyl thioester, pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolyl thioester, etc.], or an ester with a N-hydroxy compound [e.g. N,N-dimethylhydroxylamine, 1-hydroxy-2-(1H)-pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxy-1H-benzotriazole, etc.], and the like. These reactive derivatives can optionally be selected from them according to the kind of the compound (II) to be used.
Suitable salts of the compound (III) and its reactive derivative can be referred to the ones as exemplified for the compound (I).
The reaction is usually carried out in a conventional solvent such as water, alcohol [e.g. methanol, ethanol, etc.], acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or any other organic solvent which does not adversely influence the reaction. These conventional solvent may also be used in a mixture with water.
In this reaction, when the compound (II) is used in a free acid form or its salt form, the reaction is preferably carried out in the presence of a conventional condensing agent such as N,Nxe2x80x2-dicyclohexylcarbodiimide; N-cyclohexyl-Nxe2x80x2-morpholinoethylcarbodiimide; N-cyclohexyl-Nxe2x80x2-(4-diethylaminocyclohexyl)carboxiimide; N,Nxe2x80x2-diethylcarbodiimide, N,Nxe2x80x2-diisopropylcarbodiimide; N-ethyl-Nxe2x80x2-(3-dimethylaminopropyl)carbodiimide; N,Nxe2x80x2-carbonyl-bis(2-methylimidazole); pentamethyleneketene-N-cyclohexylimine; diphenylketene-N-cyclohexylimine; ethoxyacetylene; 1-alkoxy-1-chloroethylene; trialkyl phosphite; ethyl polyphosphate; isopropyl polyphosphate; phosphorus oxychloride (phosphoryl chloride); phosphorus trichloride; thionyl chloride; oxalyl chloride; lower alkyl haloformate [e.g. ethyl chloroformate, isopropyl chloroformate, etc.]; triphenylphosphine; 2-ethyl-7-hydroxybenzisoxazolium salt; 2-ethyl-5-(m-sulfophenyl)isoxazolium hydroxide intramolecular salt; 1-(p-chlorobenzenesulfonyloxy)-6-chloro-1H-benzotriazole; a combination of N-lower alkylhalopyridium halide (e.g., 1-methyl-2-chloropyridinium iodide, etc.) and tri(lower)alkylamine (e.g. triethylamine, etc.); so-called Vilsmeier reagent prepared by the reaction of N,N-dimethylformamide with thionyl chloride, phosgene, trichloromethyl chloroformate, phosphorus oxychloride, etc.; or the like.
The reaction may also be carried out in the presence of an inorganic or organic base such as an alkali metal bicarbonate, tri(lower)alkylamine (e.g. triethylamine, etc.), pyridine, N-(lower)alkylmorpholine, N,N-di(lower)alkylbenzylamine, alkali metal lower alkoxide (e.g. sodium methoxide, etc.) or the like.
The reaction temperature is not critical, and the reaction is usually carried out under cooling to warming.
Process (A)-{circle around (4)}
The compound (V) or a salt thereof can be prepared by subjecting the compound (IV) or a salt thereof to cyclization reaction.
This reaction can be carried out in the manner disclosed in Preparation 20 or similar manners thereto.
Process (A)-{circle around (2)}
The compound (VI) or a salt thereof can be prepared by subjecting the compound (V) or a salt thereof to reduction reaction.
This reaction can be carried out in the manner disclosed in Preparation 22 or similar manners thereto.
Process (A)-{circle around (3)}
The compound (IIa) or a salt thereof can be prepared by subjecting the compound (VI) or a salt thereof to dehydration reaction.
This reaction can be carried out in the manner disclosed in Preparation 24 or similar manner thereto.
It is to be noted that the object compound (I) may include one or more stereoisomer(s) due to asymmetric carbon atom(s) and double bond(s) and all such isomers and mixture thereof are included within the scope of this invention.
Regarding the object compound (I), it is to be understood that they include tautomeric isomers.
That is, a group of the formula: 
can be also alternatively represented by its tautomeric formula: 
That is, both of the said groups are in the state of equilibrium and such tautomerism can be represented by the following equilibrium. 
And it is obvious to any person skilled in the arts that both of the tautomeric isomers are easily convertible reciprocally and are included within the same category of the compound per se.
Accordingly, the both of the tautomeric forms of the object compound (I) are clearly included within the scope of the present invention.
In the present specification, the object compound including the group of such tautomeric isomers is represented by using one of the expressions therefor, that is the formula: 
only for the convenient sake.
It is further to be noted that isomerization or rearrangement of the object compound (I) may occur due to the effect of the light, acid, base or the like, and the compound obtained as the result of said isomerization or rearrangement is also included within the scope of the present invention.
It is also to be noted that the solvating form of the compound (I) (e.g. hydrate, etc.) and any form of the crystal of the compound (I) are included within the scope of the present invention.
The new guanidine derivatives (I) and a pharmaceutically acceptable salt thereof of the present invention possess a strong inhibitory activity on Na+/H+ exchange in cells and therefore are useful as an inhibitor on Na+/H+ exchange in cells.
Accordingly, the new guanidine derivatives (I) and a pharmaceutically acceptable salt thereof can be used for the expectorant and for the treatment and/or prevention of cardiovascular diseases [e.g. hypertension, angina pectoris, myocardial infarction, heart failure (e.g. congestive heart failure, acute heart failure, cardiac hypertrophy, etc.), arrhythmia (e.g. ischemic arrhythmia, arrhythmia due to myocardial infarction, arrhythmia after PTCA (percutaneous transluminal coronary angioplasty), thrombolysis or CABG (coronary artery bypass graft), etc.), restenosis after PTCA or PTA (percutaneous transluminal angioplasty), etc.], cerebrovascular diseases [e.g. ischemic stroke, hemorrhagic stroke, edema, etc.], renal diseases [e.g. diabetic nephropathy, ischemic acute renal failure, etc.], arteriosclerosis, shock [e.g. hemorrhagic shock, endotoxin shock, etc.], hyperlipidemia and the like, and can also be used as an agent for ischemic reperfusion injury, myocardial protection, organ protection in organ transplantation, in non-cardiac and cardiac surgery, and the like.
In order to show the utilities of the guanidine derivatives (I) and a pharmaceutically acceptable salt thereof of the present invention, pharmacological test data of the representative compound of the guanidine derivatives (I) are illustrated in the following.
[1] Test Compound
(a) [9-[(E)-(2-Carboxyvinyl)]-2,3-dihydro-1-benzoxepin-4-carbonyl]guanidine hydrochloride
[2] Inhibitory activity on Na+/H+ exchange in cells
[i] Test Method
Procedure was carried out according to a similar manner to the method described in Enzymology 173, 777 (1989).
Cell preparation: One male SD strain rat weighing 250-300 g was sacrificed with the blow on the head. Then, the thymus was removed into ice-cold NaCl medium (140 mM sodium chloride, 1 mM potassium chloride, 1 mM calcium chloride, 1 mM magnesium chloride, 10 mM glucose and 20 mM N-2-hydroxyethylpiperazine-Nxe2x80x2-2-ethanesulfonic acid (HEPES)xe2x80x94pH 7.3), cut in small fragments, and transferred to glass homogenizer. The cells were dissociated by gentle strokes, and the resulting suspension was filtrated through six layers of surgical gauze and the filtrate was centrifuged at 4xc2x0 C. at 1000 g for 10 minutes.
Assay: The pellet was washed with Na-free buffer (140 mM Trimethyl ammonium, 4 mM KCl, 1 mM CaCl2, 1 mM MgSO4, 1 mM NaH2PO4, 18 mM glucose, 20 mM HEPES (pH 7.4)), then incubated with 16 xcexcM of acetoxymethyl ester of 2xe2x80x2, 7xe2x80x2-bis(2-carboxyethyl)-5,6-carboxyfluorescein (BCECF-AM, Calbiochem Co.) and 20 mM NH4Cl at 37xc2x0 C. for 30 minutes. The BCECF- and NH4Cl-loaded cells were washed twice, resuspended in Na-free buffer and kept at 4xc2x0 C. Intracellular pH was measured at 37xc2x0 C. with a spectrofluorometer (FS100, Kowa company, Japan) using the ratio of the emission (530 nm) obtained at 490 nm excitation wavelengths. After addition of 10 xcexcl cell suspension into 460 xcexcl of Na-free buffer including test compound solved in dimethyl sulfoxide (final concentration of dimethyl sulfoxide was 0.1%), 25 xcexcl of 2.0 M NaCl (final 100 mM) was applied to start the reaction. The initial increase in intracellular pH in response to the added NaCl was taken as an estimate of Na+/H+ exchange activity. The BCECF fluorescence signals were calibrated by titration with 1 M 2-(N-morpholino)ethanesulfonic acid (MES) after permeabilization of the cells with 0.5% Triton.
[3] Test Result:
The object compound (I) or its pharmaceutically acceptable salts can usually be administered to mammals including human being in the form of a conventional pharmaceutical composition such as oral dosage form (e.g., capsule, micro-capsule, tablet, granule, powder, troche, syrup, aerosol, inhalation, suspension, emulsion, etc.), injection dosage form, suppository, ointment, or the like.
The pharmaceutical composition of this invention can contain various organic or inorganic carrier materials, which are conventionally used for pharmaceutical purpose such as excipient (e.g., sucrose, starch, mannit, sorbit, lactose, glucose, cellulose, talc, calcium phosphate, calcium carbonate, etc.), binding agent (e.g., cellulose, methyl cellulose, hydroxypropylcellulose, polypropylpyrrolidone, gelatin, gum arabic, polyethyleneglycol, sucrose, starch, etc.), disintegrator (e.g., starch, carboxymethyl cellulose, calcium salt of carboxymethyl cellulose, hydroxypropylstarch, sodium glycolestarch, sodium bicarbonate, calcium phosphate, calcium citrate, etc.), lubricant (e.g., magnesium stearate, talc, sodium laurylsulfate, etc.), flavoring agent (e.g., citric acid, menthol, glycine, orange powders, etc.), preservative (e.g., sodium benzoate, sodium bisulfite, methylparaben, propylparaben, etc.), stabilizer (e.g., citric acid, sodium citrate, acetic acid, etc.), suspending agent (e.g., methyl cellulose, polyvinylpyrrolidone, aluminum stearate, etc.), dispersing agent, aqueous diluting agent (e.g., water, etc.), base wax (e.g., cacao butter, polyethyleneglycol, white petrolatum, etc.).
The effective ingredient may usually be administered with a unit dose of 0.01 mg/kg to 500 mg/kg, 1 to 4 times a day. However, the above dosage may be increased or decreased according to age, weight, conditions of the patient or the administering method.
Preferred embodiments of the object compound (I) are as follows.
R1 is hydrogen or halogen (more preferably chroline),
R2 is hydroxy, lower alkoxycarbonyl(lower)alkoxy (more preferably C1-C4 alkoxycarbonyl-(C1-C4)alkoxy, most preferably methoxycarbonylmethoxy), hydroxy(lower)alkyl (more preferably hydroxy(C1-C4)alkoxy, most preferably hydroxymethyl), lower alkoxy(lower)alkyl (more preferably C1-C4 alkoxy(C1-C4)alkyl, most preferably methoxymethyl), lower alkylthio(lower)alkyl (more preferably C1-C4 alkylthio(C1-C4)alkyl, most preferably methylthiomethyl), dihalo(lower)alkyl (more preferably dihalo-(C1-C4)alkyl, most preferably difluoromethyl), trihalo(lower)alkyl (more preferably trihalo(C1-C4)alkyl, most preferably trifluoromethyl), (ethoxycarbonyl)amino, sulfamoylamino, (dimethylsulfamoyl)amino, N,N-di(lower)alkylamino(lower)alkyl (more preferably N,N-di(C1-C4)alkylamino)C1-C4)alkyl, most preferably N,N-dimethylaminomethyl), hydroxyimino(lower)alkyl (more preferably hydroxyimino(C1-C4)alkyl, most preferably hydroxyiminomethyl), lower alkoxyimino(lower)alkyl (more preferably C1-C4 alkoxyimino(C1-C4)alkyl, most preferably methoxyiminomethyl), carboxy, lower alkoxycarbonyl (more preferably C1-C4 alkoxycarbonyl, most preferably methoxycarbonyl), carbamoyl, di(lower)alkylcarbamoyl (more preferably di(C1-C4)alkylcarbamoyl, most preferably dimethylcarbamoyl), (amino(lower)alkyl)carbamoyl (more preferably (amino(C1-C4)alkyl)carbamoyl, most preferably (2-aminoethyl)carbamoyl, N,N-di(lower)alkylamino(lower)alkylcarbamoyl (more preferably N,N-di(C1-C4)alkylamino(C1-C4)-alkylcarbamoyl, most preferably (2-(dimethylamino)ethyl)carbamoyl), guanidinocarbonyl, lower alkylsulfonyl (more preferably C1-C4 alkylsulfonyl, most preferably methylsulfonyl), lower alkylsulfinyl (more preferably C1-C4 alkylsulfinyl, most preferably methylsulfinyl), morpholinylsulfonyl (more preferably morpholinosulfonyl), sulfamoyl, lower alkylsulfamoyl (more preferably C1-C4 alkylsulfamoyl, most preferably methylsulfamoyl or ethylsulfamoyl), lower alkylthio (more preferably C1-C4 alkylthio, most preferably methylthio or ethylthio), cyano, (lower alkylsulfonyl) (lower)alkyl (more preferably (C1-C4)alkylsulfonyl) (C1-C4)alkyl, most preferably (methylsulfonyl)methyl), carboxy(lower)alkenyl (more preferably carboxy(C2-C4)alkenyl, most preferably carboxyvinyl), guanidinocarbonyl(lower)alkenyl (more preferably guanidinocarbonyl(C2-C4)-alkenyl, most preferably guanidinocarbonylvinyl), aryl which has one or two hydroxy(lower)alkyl (more preferably (hydroxy(C1-C4)alkyl)phenyl, most preferably (hydroxymethyl)phenyl), or a heterocyclic group (more preferably unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 to 2 sulfur atom(s) or saturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 to 4 nitrogen atom(s), most preferably thienyl or pyrrolidinyl) which has one or two halogen or oxo (more preferably dihalothienyl (most preferably dichlorothienyl) or oxopyrrolidinyl), and
X is xe2x80x94Oxe2x80x94.
More preferred embodiments of the object compound (I) are as follows.
R1 is hydrogen or halogen,
R2 is guanidinocarbonyl or lower alkylsulfonyl, and
X is xe2x80x94Oxe2x80x94.
The following Preparations and Examples are given for the purpose of illustrating the present invention in more detail. The solvents indicated between parentheses after the melting point represent the crystallization solvents.
Preparation 1
A mixture of ethyl 2,3-dihydro-9-iodo-1-benzoxepin-4-carboxylate (0.34 g), ethyl acrylate (0.13 ml), palladium(II) acetate (2.2 mg), tri-o-tolylphosphine (6.0 mg), and triethylamine (0.15 ml) in acetonitrile (1 ml) was stirred at 100xc2x0 C. under nitrogen atmosphere for 5 hours and partitioned between ethyl acetate and water. The organic layer was washed successively with water and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was triturated in n-hexane to give a solid of ethyl 2,3-dihydro-9-[(E)-(2-ethoxycarbonylvinyl)]-1-benzoxepin-4-carboxylate (0.14 g).
mp: 96-97xc2x0 C.
IR (KBr): 1712, 1689, 1628, 1583 cmxe2x88x921 
NMR (DMSO-d6, xcex4): 1.34 (3H, t, J=7.1 Hz), 1.35 (3H, t, J=7.1 Hz), 2.95-3.1 (2H, m), 4.2-4.45 (4H, m), 6.47 (1H, d, J=16.2 Hz), 7.04 (1H, dd, J=7.7, 7.7 Hz), 7.38 (1H, dd, J=1.6, 7.7 Hz), 7.51 (1H, dd, J=1.6, 7.7 Hz), 7.58 (1H, s), 8.08 (1H, d, J=16.2 Hz)
APCI-MS: 317 [M+H]+
Preparation 2
The following compound was obtained according to a similar manner to that of Preparation 1.
Ethyl 9-[(E)-(2-tert-butoxycarbonylvinyl)]-2,3-dihydro-1-benzoxepin-4-carboxylate
NMR (CDCl3, xcex4): 1.35 (3H, t, J=7.1 Hz), 1.54 (9H, s), 2.9-3.05 (2H, m), 4.28 (2H, q, J=7.1 Hz), 4.3-4.4 (2H, m), 6.39 (1H, d, J=16.1 Hz), 7.02 (1H, dd, J=7.7, 7.7 Hz), 7.36 (1H, dd, J=1.5, 7.7 Hz), 7.50 (1H, dd, J=1.5, 7.7 Hz), 7.57 (1H, s), 7.99 (1H, d, J=16.1 Hz)
Preparation 3
To a solution of ethyl 9-[(E)-(2-tert-butoxycarbonylvinyl)]-2,3-dihydro-1-benzoxepin-4-carboxylate (0.56 g) was added trifluoroacetic acid (0.63 ml) at 0xc2x0 C. The reaction mixture was stirred overnight at ambient temperature and evaporated in vacuo. The residue was triturated with diisopropyl ether to give a solid of ethyl 9-[(E)-(2-carboxyvinyl)]-2,3-dihydro-1-benzoxepin-4-carboxylate (0.3 g).
mp: 166-168xc2x0 C.
IR (KBr): 1703, 1682, 1620, 1581 cmxe2x88x921 
NMR (DMSO-d6, xcex4): 1.28 (3H, t, J=7.1 Hz), 2.85-3.0 (2H, m), 4.21 (2H, q, J=7.1 Hz), 4.3-4.45 (2H, m), 6.53 (1H, d, J=16.2 Hz), 7.10 (1H, dd, J=7.7, 7.7 Hz), 7.53 (1H, s), 7.55-7.65 (1H, m), 7.65-7.8 (1H, m), 7.92 (1H, d, J=16.2 Hz)
APCI-MS: 289 [M+H]+
Preparation 4
The following compound was obtained according to a similar manner to that of Preparation 3.
Ethyl 9-carboxymethoxy-2,3-dihydro-1-benzoxepin-4-carboxylate
mp: 100-101xc2x0 C.
IR (KBr): 1740, 1700 cmxe2x88x921 
NMR (DMSO-d6, xcex4): 1.27 (3H, t, J=7.1 Hz), 2.8-2.95 (2H, m), 4.1-4.35 (2H, m), 4.68 (2H, s), 6.85-7.15 (3H, m), 7.50 (1H, s), 12.99 (1H, br s)
APCI-MS: 293 [M+H]+
Preparation 5
A mixture of ethyl 2,3-dihydro-9-iodo-1-benzoxepin-4-carboxylate (1.03 g), 2-formylbenzeneboronic acid (0.49 g), tetrakis(triphenylphosphine)palladium(0) (0.35 g), and triethylamine (0.92 ml) in N,N-dimethylformamide (10.3 ml) was stirred at 100xc2x0 C. under nitrogen atomsphere for 2.5 hours and partitioned between ethyl acetate and water. The organic layer was washed successively with 1N hydrochloric acid, saturated aqueous sodium bicarbonate, and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was purified by medium pressure liquid chromatography (silica gel) using a mixture of ethyl acetate and n-hexane (1:30xcx9c1:9) to give a solid of ethyl 2,3-dihydro-9-(2-formylphenyl)-1-benzoxepin-4-carboxylate (0.63 g).
mp : 83-85xc2x0 C.
IR (KBr) : 1695, 1633, 1595 cmxe2x88x921 
NMR (CDCl3, xcex4) : 1.35 (3H, t, J=7.1Hz), 2.8-3.0 (2H, m), 4.05-4.25 (2H, m), 4.28 (2H, q, J=7.1Hz), 7.14 (1H, dd, J=7.5, 7.5Hz), 7.2-7.35 (2H, m), 7.35-7.55 (2H, m), 7.6-7.75 (2H, m), 7.95-8.1 (1H, m), 9.84 (1H, s)
Preparation 6
The following compound was obtained according to a similar manner to that of Preparation 5.
Ethyl 9-(2,5-dichloro-3-thienyl)-2,3-dihydro-1-benzoxepin-4-carboxylate
IR (Film) : 1703, 1633 cmxe2x88x921 
NMR (DMSO-d6, xcex4) : 1.35 (3H, t, J=7.1Hz), 2.9-3.05 (2H, m), 4.2-4.4 (4H, m), 6.82 (1H, s), 7.05-7.15 (1H, m), 7.2-7.45 (2H, m), 7.62 (1H, s)
APCI-MS : 369, 371 [M+H]+
Preparation 7
To a solution of ethyl 2,3-dihydro-9-(2-formylphenyl)-1-benzoxepin-4-carboxylate (0.58 g) in a mixture of ethanol (5.8 ml) and tetrahydrofuran (3 ml) was added sodium borohydride (34 mg) at 0  C. The reaction mixture was stirred for 30 minutes at ambient temperature, thereto was added 1N hydrochloric acid (2 ml), and evaporated in vacuo. The residue was partitioned between ethyl acetate and water. The organic layer was washed successively with saturated aqueous sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, and evaporated n vacuo. The residue was purified by medium pressure liquid chromatography (silica gel) using a mixture of ethyl acetate and n-hexane (1:9) as an eluent to give a solid of ethyl 2,3-dihydro-9-(2-hydroxymethylphenyl)-1-benzoxepin-4-carboxylate (530 mg).
mp : 94-95xc2x0 C.
IR (KBr) : 3357, 1703, 1631 cmxe2x88x921 
NMR (DMSO-d6, xcex4) : 1.35 (3H, t, J=7.1Hz), 1.92 (1H, br s), 2.85-3.0 (2H, m), 3.95-4.2 (2H, m), 4.28 (2H, q, J=7.1Hz), 4.35-4.55 (2H, m), 7.05-7.25 (3H, m), 7.3-7.5 (3H, m), 7.5-7.6 (1H, m), 7.65 (1H, s)
APCI-MS : 307 [M+Hxe2x88x92H2O]+
Preparation 8
To a mixture of ethyl 2,3-dihydro-9-hydroxy-1-benzoxepin-4-carboxylate (1.17 g) and potassium carbonate (0.67 g) in N,N-dimethylformamide (11.7 ml) was added tert-butyl bromoacetate (0.74 ml) at ambient temperature. The reaction mixture was stirred overnight at the same temperature and partitioned between ethyl acetate and waster. The organic layer was washed successively with water and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was triturated with petroleum ether to give a solid of ethyl 9-tert-butoxycarbonylamethoxy-2,3-dihydro-1-benzoxepin-4-carboxylate (1.63 g).
m; : 87-88xc2x0 C.
IR (KBr) : 1745, 1697, 1637 cmxe2x88x921 
NMR (DMSO-d6, xcex4) : 1.35 (3H, t, J=7.1Hz, 1.47 (9H, s), 2.95-3.05 (2H, m), 4.27 (2H, q, J=7.1Hz), 4.3-4.4 (2H, m), 4.58 (2H, s), 6.82 (1H, dd, J=2.0, 7.8Hz), 6.92 (1H, dd, J=7.8, 7.8Hz), 7.00 (1H, dd, J=2.0, 7.8Hz), 7.57 (1H, s)
Preparation 9
To a mixture of sodium ethoxide (1.7 ml, 20% in ethanol) and dichlorobis(triphenylphosphine)palladium(II) (14 mg) in dichloromethane (7 ml) was added a mixture of ethyl 2,3-dihydro-9-iodo-1-benzoxepin-4-carboxylate (0.69 g) and ethyl formate (0.28 ml) at ambient temperature under nitrogen atmosphere. The reaction mixture was stirred at 40xc2x0 C. for 3 hours and filtered off. The filtrate was partitioned between diethyl ether and 1N hydrochloric acid. The organic layer was washed successively with saturated aqueous sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was purified by medium pressure liquid chromatography (silica gel) using a mixture of ethyl acetate and n-hexane (1:19) as an eluent to give a solid of ethyl 2,3-dihydro-9-ethoxycarbonyl-1-benzoxepin-4-carboxylate (120 mg).
IR (Film) : 1726, 1709, 1631, 1585 cmxe2x88x921 
NMR (CDCl3, xcex4) : 1.35 (3H, t, J=7.1Hz,), 1.39 (3H, t, J=7.1Hz), 2.9-3.1 (2H, m), 4.2-4.45 (6H, m), 7.0-7.15 (1H, m), 7.4-7.5 (1H, m), 7.59 (1H, s), 7.6-7.7 (1H, m)
APCI-MS : 291 [M+H]+
Preparation 10
To a mixture of ethyl 2,3-dihydro-9-hydroxy-1-benzoxepin-4-carboxylate (1.17 g) and triethylamine (0.14 ml) in dichloromethane (12 ml) was added dropwise trifluoromethanesulfonic anhydride (0.93 ml) under ice-sodium chloride cooling. The reaction mixture was stirred at 0xc2x0 C. for 4 hours, poured into water, and adjusted to pH 10 with 20% aqueous potassium carbonate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was purified by medium pressure liquid chromatography (silica gel) using a mixture of ethyl acetate and n-hexane (1:30) to give a solid of ethyl 2,3-dihydro-9-trifluoromethanesulfonyloxy-1-benzoxepin-4-carboxylate (1.44 g).
mp : 52-53xc2x0 C.
IR (KBr) : 1703 cmxe2x88x921 
NMR (CDCl3, xcex4) : 1.36 (3H, t, J=7.1Hz), 2.95-3.1 (2H, m), 4.29 (2H, q, j=7.1Hz), 4.3-4.4 (2H, m), 7.04 (1H, dd, J=7.9, 7.9Hz), 7.19 (1H, dd, J=1.7, 8.1Hz), 7.35 (1H, dd, J=1.7, 7.8Hz), 7.58 (1H, s)
APCI-MS : 367 [M+H]+
Preparation 11
A mixture of zinc (69.2 mg, powder) and potassium cyanide (0.12 g) in N,N-dimethylformamide (10.5 ml) was stirred for 10 minutes under nitrogen atmosphere at ambient temperature and thereto was added successively ethyl 2,3-dihydro-9-trifluoromethanesulfonyloxy-1-benzoxepin-4-carboxylate (0.53 g), triethylamine (0.25 ml), and [1,1xe2x80x2-bis(diphenylphosphino)ferrocene]-dichloropalladium (0.12 g, complex with dichloromethane (1:1)). The reaction mixture was stirred at 60xc2x0 C. for 2 hours. Thereto was added a mixture of ethyl acetate and water, basified by aqueous potassium carbonate, and filtered off. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was purified by medium pressure liquid chromatography (silica gel) using a mixture of ethyl acetate and n-hexane (1:9) to give a solid of ethyl 9-cyano-2,3-dihydro-1-benzoxepin-4-carboxylate (310 mg).
mp : 113-114xc2x0 C.
IR (KBr) : 2233, 1699, 1635, 1583 cmxe2x88x921 
NMR (CDCl3, xcex4) : 1.36 (3H, t, J=7.1Hz), 2.95-3.1 (2H, m), 4.29 (2H, q, J6=7.1Hz), 2.95-3.1 (2H, m), 4.29 (2H, q, J=7.1Hz), 4.35-4.5 (2H, m), 7.0-7.15 (1H, m), 7.30 (1H, br s), 7.45-7.6 (3H, m)
APCI-MS : 244 [M+H]+
Preparation 12
To a mixture of ethyl 2,3-dihydro-9-iodo-1-benzoxepin-4-carboxylate (5.62 g), potassium carbonate (9.03 g), and palladium(II) acetate (0.73 g) in aqueous N,N-dimethylformamide (48 ml, 67% v/v) was introduced carbon monoxide for 30 minutes. The reaction mixture was stirred for 2 days at ambient temperature in an atmosphere of carbon monoxide and partitioned between ethyl acetate and water. The aqueous layer was acidified with 1H hydrochloric acid and extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium thiosulfate and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo to give a solid of ethyl 9-carboxy-2,3-dihydro-1-benzoxepin-4-carboxylate (3.8 g).
mp : 132-134xc2x0 C.
IR (KBr) : 1729, 1697, 1637 cmxe2x88x921 
NMR (DMSO-d6, xcex4) : 1.28 (3H, t, J=7.1Hz), 2.85-3.0 (2H, m), 4.21 (2H, q, J=7.1Hz), 4.25-4.35 (2H, m), 7.11 (1H, dd, J=7.6, 7.6Hz), 7.5-7.6 (1H, m), 7.55 (1H, s), 7.65 (1H, dd, J=1.6, 7.8Hz)
APCI-MS : 263 [M+H]+
Preparation 13
To a mixture of ethyl 9-carboxy-2,3-dihydro-1-benzoxepin-4-carboxylate (0.52 g) and triethylamine (0.33 ml) in tetrahydrofuran (5.2 ml) was added dropwise isobutyl chloroformate (0.31 ml) below 5xc2x0 C. under ice-sodium chloride cooling. The reaction mixture was stirred for 30 minutes at the same temperature. The resulting precipitate was filtered off and washed with cold tetrahydrofuran. The filtrate was added to a solution of sodium borohydride (75 mg) in aqueous tetrahydrofuran (10 ml, 90% v/v) at 0xc2x0 C. The reaction mixture was stirred for 30 minutes at the ambient temperature and evaporated in vacuo. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was purified by medium pressure liquid chromatography (silica gel) using a mixture of ethyl acetate and n-hexane (1:9) to give a solid of ethyl 2,3-dihydro-9-hydroxymethyl-1-benzoxepin-4-carboxylate (0.37 g).
mp : 75-76xc2x0 C.
IR (KBr) : 3280, 1700 cmxe2x88x921 
NMR (CDCl3, xcex4) : 1.35 (3H, t, J=7.1Hz), 2.2-2.35 (1H, m), 2.95-3.05 (2H, m), 4.28 (2H, q, J=7.1Hz), 4.3-4.4 (2H, m), 4.71 (2H, d, J=5.9Hz), 6.95-7.1 (1H, m), 7.25-7.35 (2H, m), 7.55-7.65 (1H, m)
APCI-MS : 231 [M+Hxe2x88x92H2O]+
Preparation 14
A mixture of ethyl 2,3-dihydro-9-hydroxymethyl-1-benzoxepin-4-carboxylate (0.45 g) and manganese (IV) oxide (4.5 g) was stirred under reflux for 1 hour and filtered off. The filtrate was evaporated in vacuo to give a solid of ethyl 2,3-dihydro-9-formyl-1-benzoxepin-4-carboxylate (0.43 g).
mp : 111-112xc2x0 C.
IR (KBr) : 1701, 1670, 1631, 1577 cmxe2x88x921 
NMR (CDCl3, xcex4) : 1.37 (3H, t, J=7.1Hz), 2.95-3.1 (2H, m), 4.29 (2H, q, J=7.1Hz), 4.35-4.5 (2H, m), 7.05-7.2 (1H, m), 7.55-7.65 (2H, m), 7.75-7.85 (1H, m), 10.53 (1H, s)
APCI-MS ; 247 [M+H]+
Preparation 15
A mixture of ethyl 2,3-dihydro-9-formyl-1-benzoxepin-4-carboxylate (0.40 g), hydroxylamine hydrochloride (0.14 g), and pyridine (0.16 ml) in ethanol (8 ml) was stirred under reflux for 40 minutes and evaporated in vacuo. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was triturated with diisopropyl ether to give a solid of ethyl 2,3-dihydro-9-hydroxyiminomethyl-1-benxoepin-4-carboxylate (0.22 g).
mp : 145-146xc2x0 C.
IR (KBr) : 3367, 1682, 1637, 1585 cmxe2x88x921 
NMR (CDCl3, xcex4) : 1.28 (3H, t, J=7.1Hz), 2.8-3.0 (2H, m), 4.21 (2H, q, J=7.1Hz), 4.25-4.4 (2H, m), 7.0-7.15 (1H, m), 7.53 (1H, s), 7.5-7.6 (1H, m), 7.65-7.75 (1H, m), 8.36 (1H, s), 11.33 (1H, br s)
APCI-MS : 262 [M+H]+
Preparation 16
To a mixture of 9-carboxy-2,3-dihydro-1-benzoxepin-4-carboxylate (0.39 g), N,N-dimethylethylenediamine (0.163 ml), and 1-hydroxybenzotriaole hydrate (0.22 g) in dichloromethane (8 ml) was added 1-(3-dimethylamino-propyl)-3-ethylcarbodiimide hydrochloride (0.31 g). The reaction mixture was stirred for 4.5 hours at ambient temperature and evaporated in vacuo. The residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was washed successively with water and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo to give a solid of ethyl 2,3-dihydro-9-[2-(N,N-dimethylamino)-ethylaminocarbonyl]-1-benzoxepin-4-carboxylate (0.39 g),
mp : 80-81xc2x0 C.
IR (KBr) : 3359, 1701, 1658, 1631 cmxe2x88x921 
NMR (DMSO-d6, xcex4) : 1.28 (3H, t, J=7.1Hz), 2.20 (6H, s), 2.40 (2H, t, J=6.7Hz), 2.85-2.95 (2H, m), 3.25-3.4 (2H, m), 4.22 (2H, q, J=7.1Hz), 4.25-4.35 (2H, m), 7.13 (1H, dd, J=7.6, 7.6Hz), 7.5-7.7 (3H, m), 8.25-8.4 (1H, m)
APCI-MS : 333 [M+H]+
Preparation 17
To a mixture of ethyl 2,3-dihydro-7-iodo-1-benzoxepin-4-carboxylate (0.69 g), triethylamine (1.12 ml), 1,3-bis(diphenylphosphino)propane (0.165 g), and palladium(II) acetate (90 mg) in N,N-dimethylformamide (6.4 ml) was introduced carbon monoxide for 30 minutes. The reaction mixture was stirred for 5 hours at 95xc2x0 C. in an atmosphere of carbon monoxide and partitioned between ethyl acetate and water. The organic layer was washed successively with saturated aqueous sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was purified by medium pressure liquid chromatography (silica gel) using a mixture of ethyl acetate and n-hexane (1:4) to give a solid of ethyl 2,3-dihydro-7-methoxycarbonyl-1-benzoxepin-4-carboxylate (0.45 g).
mp : 79-81xc2x0 C.
IR (KBr) : 1710, 1699, 1606 cmxe2x88x921 
NMR (DMSO-d6, xcex4) : 1.36 (3H, t, J=7.1Hz), 2.95-3.1 (2H, m), 3.91 (3H, s), 4.28 (2H, q, J=7.1Hz), 4.3-4.4 (2H, m), 7.00 (1H, d, J=8.5Hz), 7.62 (1h, s), 7.90 (1H, dd, J=2.2, 8.5Hz), 8.07 (1H, d, J=2.1Hz)
APCI-MS : 277 [M+H]+
Preparation 18
A solution of ethyl 3-amino-2-(3-ethoxycarbonyl-propoxy)benzoate (8.93 g) in conc. hydrochloric acid (4.8 ml) was cooled in an ice bath. To this solution was added dropwise a solution of sodium nitrite (2.11 g) in water (5 ml) at 5xc2x0 C. On the other hand, a solution of potassium xanthogenate (5.83 g) in water (7.6 ml) was heated at 50xc2x0 C. To this solution was added dropwise the above solution of the diazonium salt at 50-55xc2x0 C. The reaction mixture was cooled to room temperature and was extracted with ethyl acetate. After an additional extraction with ethyl acetate, the combined extracts were dried over magnesium sulfate and evaporated in vacuo to give the crude material, which was then dissolved in ethanol and 85% potassium hydroxide (9.10 g) was added to the solution. After the mixture was heated to reflux for 1.5 hours, it was cooled in an ice bath and acidified with conc. hydrochloric acid. The mixture was then extracted with ethyl acetate (x 3). The combined extracts were dried over magnesium sulfate and evaporated in vacuo to give 3-mercapto-2-(3-carboxypropoxy)benzoic acid (7.08 g) as yellow crystals.
A mixture of the mercaptobenzoic acid (7.08 g), potassium carbonate (4.26 g) and iodomethane (6.44 g) in acetone (70 ml) was heated to reflux under nitrogen atmosphere for 4 hours. Acetone was evaporated in vacuo and the residue was partitioned between water and ethyl acetate. After an additional extraction with ethyl acetate, the combined extracts were washed with water, dried over magnesium sulfate, and evaporated in vacuo to give 1.64 g of the crude material. The aqueous layer was acidified with 1N hydrochroric acid. The precipitates were collected by filtration, washed with water, and dried to give 5.22 g of rude material. The combined crude material (6.896 g) was purified by column chromatography on silica gel using a mixture of chloroform and methanol (10:1) to give light brown crystals of 3-methylthio-2-(3-carboxypropoxy)benzoic acid (5.21 g).
mp : 162-164xc2x0 C. (ethyl acetate)
IR (Nujol) : 1695, 1585, 1560 cmxe2x88x921 
NMR (DMSO-d6, xcex4) : 1.87-2.00 (2H, m), 2.41 (3H, s), 2.48-2.51 (2H, m), 3.95 (2H, t, J=6.2Hz), 7.19 (1H, t, J=7.7Hz), 7.35 (1H, dd, J=7.7, 1.7Hz), 7.44 (1H, dd, J=7.7, 1.7Hz)
Preparation 19
A solution of 3-methylthio-2-(3-carboxypropoxy)-benzoic acid (4.80 g) and conc. sulfuric acid (1.0 ml) in ethanol (96 ml) was heated to reflux for 19 hours. Ethanol was evaporated in vacuo, and the residue was partitioned between 1N sodium hydroxide and ethyl acetate. After an additional extraction with ethyl acetate, the combined extracts were washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The crude material was purified by column chromatography on silica gel using a mixture of n-hexane and ethyl acetate (10:1) to give ethyl 3-methylthio-2-(3-ethoxycarbonylpropoxy)-benzoate (5.20 g) as an oil.
IR (Film) : 2925, 1720, 1585, 1560 cmxe2x88x921 
NMR (CDCl3, xcex4) : 1.27 (3H, t, J=7.1Hz), 1.39 (3H, t, J=7.1Hz, 2.07-2.22 (2H, m), 2.42 (3H, s), 2.64 (2H, t, J=7.5Hz), 4.05 (2H, t, J=6.1Hz), 4.16 (2H, q, J=7.1Hz), 4.37 (2H, q, J=7.1Hz), 7.13 (1H, t, J=7.7Hz), 7.28 (1H, dd, J=7.7, 1.7Hz), 7.57 (1H, dd, J=7.7, 1.7Hz)
APCI-MS : 327 [M+H]+
Preparation 20
To a solution of ethyl 3-methylthio-2-(3-ethoxycarbonylpropoxy)benzoate (3.83 g) in a mixture of ethanol (34 xcexcl) and N,N-dimethylformamide (40 ml) was added 60% sodium hydroxide (1.03 mg) at 5xc2x0 C. After the mixture was allowed to stir at room temperature for 15.5 hours, it was poured into ice-water and extracted with ethyl acetate (x 3). The combined extracts were washed with water (x 2) and brine, dried over magnesium sulfate, and evaporated in vacuo. The crude product was purified by column chromatography on silica gel using a mixture of n-hexane and ethyl acetate (20:1) to give ethyl 9-methylthio-5-oxo-2,3,4,5-tetrahydro-1-benzoxepin-4-carboxylate (2.61 g, colorless crystals).
mp : 89-90xc2x0 C. (ethyl acetatexe2x80x94diisopropyl ether)
IR (Nujol) : 1740, 1675, 1640, 1590, 1560 cmxe2x88x921 
NMR (CDCl6, xcex4) : 1.23 (3H, t, J=7.1Hz), 2.45 (3H, s), 2.52-2.61 (2H, m), 4.02-4.52 (4H, m), 4.54-4.61 (1H, m), 7.12 (1H, t, J=7.7Hz), 7.29 (1H, dd, J=7.7, 1.7Hz), 7.58 (1H, dd, J=7.7, 1.7Hz)
Anal. Calcd. for C14H16O4S : C 59.98, H 5.75 Found : C 59.73, H 5.74
Preparation 21
The following compounds were obtained according to a similar manner to that of Preparation 20.
(1) Ethyl 2,3,4,5-tetrahydro-9-hydroxy-5-oxo-1-benzoxepin-4-carboxylate
IR (Film) : 3400, 1715, 1665, 1575 cmxe2x88x921 
NMR (CDCl3, xcex4) : 1.15-1.45 (3H, m), 2.35-2.75 (2H, m), 4.0-4.6 (6H, m), 5.85-6.05 (1H, m), 7.05-7.2 (1H, m), 6.95-7.45 (3H, m)
APCI-MS : 251 [M+H]+
(2) Ethyl 2,3,4,5-tetrahydro-5-oxo-9-iodo-1-benzoxepin-4-carboxylate
IR (Film) : 1730, 1675, 1580 cmxe2x88x921 
NMR (CDCl3, xcex4) : 1.22 (3H, t, J=7.1Hz), 2.45-2.75 (2H, m), 4.0-4.45 (4H, m), 4.45-4.65 (1H, m), 6.89 (1H, dd, J=7.8, 7.8Hz), 7.77 (1H, dd, J=1.7, 7.8Hz), 7.95 (1H, dd, J=1.7, 7.8Hz)
APCI-MS : 361 [M+H]+
(3) Ethyl 7-iodo-4oxo-2,3,4,5-tetrahydro-1-benzoxepin-4-carboxylate
mp : 82-85xc2x0 C.
IR (KBr) : 1743, 1683 cmxe2x88x921 
NMR (CDCl3, xcex4) : 1.2-1.4 (3H, m), 2.55-2.75 (2H, m), 4.1-4.5 (4H, m), 6.7-7.1 (2H, m), 7.55-8.0 (1H, m), 8.1-8.3 (1H, m)
APCI-MS : 361 [M+H]+
Preparation 22
To a suspension of ethyl 9-methylthio-5-oxo-2,3,4,5-tetrahydro-1-benzoxepin-4-carboxylate (2.48 g) in ethanol (25 ml) was added sodium borohydride (248 mg) at 5xc2x0 C. After the mixture was stirred at the same temperature for 1 hour, it was warmed up to room temperature and stirred for 30 minutes. The reaction mixture was cooled in an ice bath, quenched with 1N hydrochloric acid, and partitioned between brine and ethyl acetate. After an additional extraction with ethyl acetate, the combined extracts were washed with brine, dried over magnesium sulfate, and evaporated in vacuo to give an oil, which was purified by column chromatography on silica gel using a mixture of n-hexane and ethyl acetate (5:1) to afford cis and trans mixture of ethyl 5-hydroxy-9-methylthio-2,3,4,5-tetrahydro-1-benzoxepin-4-carboxylate (1.66 g) as an oil.
IR (Film): 3430, 1718, 1560 cmxe2x88x921 
NMR (CDCl3, xcex4): 1.19-1.26 (3H, m), 2.17-2.30 (2H, m), 2.40 (3H, s), 2.78-3.04 (2H, m), 3.79-4.37 (4H, m), 5.16-5.20 (1H, m), 7.02-7.16 (3H, m)
Preparation 23
The following compounds were obtained according to a similar manner to that of Preparation 22.
(1) Ethyl 2,3,4,5-tetrahydro-5,9-dihydroxy-1-benzoxepin-4-carboxylate
IR (Film): 3300, 1700, 1585 cmxe2x88x921 
NMR (CDCl3, xcex4): 1.15-1.35 (3H, m), 2.1-3.1 (3H, m), 3.8-4.4 (5H, m), 5.1-5.2 (1H, m), 5.8-6.0 (1H, m), 6.8-7.05 (3H, m)
APCI-MS: 235 [M+H-H2O]+
(2) Ethyl 2,3,4,5-tetrahydro-5-hydroxy-9-iodo-1-benzoxepin-4-carboxylate
IR (Film): 3470, 1715 cmxe2x88x921 
NMR (CDCl3, xcex4): 1.1-1.3 (3H, m), 2.1-2.9 (2H, m), 2.95-3.1 (1H, m), 3.75-4.35 (5H, m), 5.1-5.25 (1H, m), 6.75-6.9 (1H, m), 7.3-7.55 (1H, m), 7.65-7.75 (1H, m)
APCI-MS: 362 [M+H]+, 345 [M+H-H2O]+
(3) Ethyl 7-iodo-5-hydroxy-2,3,4,5-tetrahydro-1-benzoxepin-4-carboxylate
IR (Film): 3470 (br), 1739, 1724, 1709 cmxe2x88x921 
NMR (CDCl3, xcex4): 1.15-1.35 (3H, m), 2.1-2.45 (1H, m), 2.5-3.15 (1H, m), 3.3-3.45 (1H, m), 4.0-4.35 (4H, m), 5.05-5.25 (1H, m), 6.7-6.8 (1H, m), 7.4-7.45 (1H, m), 7.65-7.9 (1H, m)
APCI-MS: 345 [M+H-H2O]+
Preparation 24
A solution of p-toluenesulfonic acid monohydrate (109 mg) and ethyl 5-hydroxy-9-methylthio-2,3,4,5-tetrahydro-1-benzoxepin-4-carboxylate (cis and trans mixture, 1.62 g) in toluene (32 ml) was heated to reflux for 1.5 hours. The reaction mixture was diluted with ethyl acetate, washed successively with saturated aqueous sodium hydrogen carbonate and brine, dried over magnesium sulfate, and evaporated in vacuo to give 1.60 g of crude product, which was purified by column chromatography on silica gel using a mixture of n-hexane and ethyl acetate (30:1) to afford ethyl 2,3-dihydro-9-methylthio-1-benzoxepin-4-carboxylate (1.30 g, colorless needles).
mp: 54-55xc2x0 C. (n-hexanexe2x80x94diisopropyl ether)
IR (Nujol): 1690 cmxe2x88x921 
NMR (CDCl3, xcex4): 1.35 (3H, t, J=7.1 Hz), 2.43 (3H, s), 3.00 (2H, t, J=5.0 Hz), 4.27 (2H, q, J=7.1 Hz), 4.37 (2H, t, J=5.0 Hz), 6.98-7.17 (3H, m), 7.56 (1H, s)
Anal. Calcd. for C14H16O3S: C 63.61, H 6.10 Found: C 63.74, H 6.13
Preparation 25
In following compound was obtained according to a similar manner to that of Preparation 24.
(1) Ethyl 2,3-dihydro-9-hydroxy-1-benzoxepin-4-carboxylate
mp: 85-86xc2x0 C.
IR (Nujol): 3360, 1680, 1615 cmxe2x88x921 
NMR (CDCl3, xcex4): 1.35 (3H, t, J=7.1 Hz), 2.95-3.1 (2H, m), 4.28 (2H, q, J=7.1 Hz), 4.3-4.4 (2H, m), 5.93 (1H, s), 6.8-7.0 (3H, m), 7.57 (1H, br s)
APCI-MS: 235 [M+H]+
(2) Ethyl 2,3-dihydro-9-iodo-1-benzoxepin-4-carboxylate
IR (Film): 1695, 1630 cmxe2x88x921 
NMR (CDCl3, xcex4): 1.35 (3H, t, J=7.1 Hz), 2.95-3.05 (2H, m), 4.28 (2H, q, J=7.1 Hz), 4.25-4.4 (2H, m), 6.76 (1H, dd, J=7.7, 7.7 Hz), 7.32 (1H, dd, J=1.5, 7.7 Hz), 7.51 (1H, s), 7.75 (1H, dd, J=1.5, 7.7 Hz)
APCI-MS: 345 [M+H]+
(3) Ethyl 2,3-dihydro-7-iodo-1-benzoxepin-4-carboxylate
mp: 70-72xc2x0 C.
IR (KBr): 1703, 1633 cmxe2x88x921 
NMR (CDCl3, xcex4): 1.35 (3H, t, J=7.1 Hz), 2.9-3.05 (2H, m), 4.14-4.35 (4H, m), 6.73 (1H, dd, J=8.6 Hz), 7.45 (1H, s), 7.48 (1H, dd, J=2.2, 8.6 Hz), 7.64 (1H, d, J=2.2 Hz)
APCI-MS: 345 [M+H]+
Preparation 26
A mixture of ethyl 9-amino-2,3-dihydro-1-benzoxepin-4-carboxylate (0.35 g), 4-chlorobutyryl chloride (0.202 ml) and pyridine (0.146 ml) in dichloromethane (3.5 ml) was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate, and the solution was washed successively with 1N hydrochloric acid, saturated aqueous sodium bicarbonate solution and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel using a mixture of n-hexane and ethyl acetate (3:1) as an eluent to give colorless crystals of ethyl 9-(4-chlorobutyryl)amino-2,3-dihydro-1-benzoxepin-4-carboxylate (0.48 g).
mp: 98-99xc2x0 C.
IR (KBr): 1695, 1662, 1635 cmxe2x88x921 
NMR (CDCl3, xcex4): 1.35 (3H, t, J=7.1 Hz), 2.1-2.35 (2H, m), 2.62 (2H, t, J=7.1 Hz), 2.95-3.10 (2H, m), 3.68 (2H, t, J=6.2 Hz), 4.28 (2H, q, J=7.1 Hz), 4.35-4.45 (2H, m), 6.95-7.10 (2H, m), 7.57 (1H, s), 7.99 (1H, br s), 8.30-8.50 (1H, m)
APCI-MS: 338 [M+H]+
Preparation 27
To a solution of ethyl 9-(4-chloro-1-oxobutylamino)-2,3-dihydro-1-benzoxepin-4-carboxylate (0.44 g) in N,N-dimethylformamide (4.4 ml) was added sodium hydride (0.17 g, 60%) at ambient temperature. The reaction mixture was stirred for 1.5 hours at the same temperature and partitioned between ethyl acetate and 1N hydrochloric acid. The organic layer was washed successively with water and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was purified by medium pressure liquid chromatography (silica gel) using a mixture of ethyl acetate and n-hexane (1:4xcx9c1:1) to give a solid of ethyl 2,3-dihydro-9-(2-oxo-1-pyrrolidinyl)-1-benzoxepin-4-carboxylate (0.21 g).
mp: 64-66xc2x0 C.
IR (KBr): 1699, 1676, 1633 cmxe2x88x921 
NMR (CDCl3, xcex4): 1.35 (3H, t, J=7.1 Hz), 2.1-2.3 (2H, m), 2.5-2.65 (2H, m), 2.9-3.05 (2H, m), 3.7-3.85 (2H, m), 4.2-4.35 (2H, m), 6.95-7.1 (1H, m), 7.15-7.35 (2H, m), 7.59 (1H, s)
APCI-MS: 302 [M+H]+
Preparation 28
A mixture of ethyl 3-benzyloxy-2-(3-ethoxycarbonylpropyloxy)benzoate (2.5 g) and palladium on charcoal (0.25 g) in ethanol (12.5 ml) was hydrogenated under hydrogen atmosphere. The catalyst was filtered off. The filtrate was evaporated in vacuo. The residue was purified by silica gel column chromatography using a mixture of ethyl acetate and n-hexane (1:3) to give colorless oil of ethyl 3-hydroxy-2-(3-ethoxycarbonylpropyloxy)benzoate (1.86 g).
IR (Film): 3380, 1710, 1585 cmxe2x88x921 
NMR (CDCl3, xcex4): 1.27 (3H, t, J=7.1 Hz), 1.39 (3H, t, J=7.1 Hz), 2.1-2.25 (2H, m), 2.55-2.7 (2H, m), 4.06 (2H, t, J=5.8 Hz), 4.19 (2H, q, J=7.1 Hz), 4.36 (2H, q, J=7.1 Hz), 5.10 (2H, s), 7.0-7.1 (1H, m), 7.14 (1H, dd, J=1.9, 8.0 Hz), 7.36 (1H, dd, J=1.9, 7.7 Hz)
Preparation 29
To a mixture of ethyl 3-hydroxy-2-(3-ethoxycarbonylpropyloxy)benzoate (1.50 g) and imidazole (0.52 g) in N,N-dimethylformamide (7.5 ml) was added tert-butyldimethylsilyl chloride (0.82 g) at ambient temperature. The reaction mixture was stirred for 2.5 hours at the same temperature and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was purified by medium pressure liquid chromatography (silica gel) using a mixture of ethyl acetate and n-hexane (1:9) to give colorless oil of ethyl 3-tert-butyldimethylsilyloxy)-2-(3-ethoxycarbonylpropyloxy)benzoate (1.97 g).
IR (Film): 1715, 1570 cmxe2x88x921 
NMR (CDCl3, xcex4): 0.20 (6H, s), 1.01 (9H, s), 1.26 (3H, t, J=7.1 Hz), 1.38 (3H, t, J=7.1 Hz), 2.0-2.2 (2H, m), 2.45-2.6 (2H, m), 4.05 (2H, t, J=6.5 Hz), 4.14 (2H, q, J=7.1 Hz), 4.36 (2H, q, J=7.1 Hz), 6.95-7.05 (2H, m), 7.25-7.35 (1H, m)
Preparation 30
70% m-Chloroperbenzoic acid (35.1 g) was added to a solution of ethyl 2,3-dihydro-9-methylthio-1-benzoxepin-4-carboxylate (15.0 g) in dichloromethane (300 ml) at 5xc2x0 C. The mixture was stirred at 5-15xc2x0 C. for 2 hours, and poured into a mixture of aqueous sodium thiosulfate (20 g/200 ml) and aqueous saturated sodium bicarbonate (200 ml). The organic layer was separated, and the aqueous layer was extracted with dichloromethane (200 ml). The extracts were combined and washed successively with saturated aqueous sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of chloroform and ethyl acetate (20:1) to give 14.6 g of colorless crystals, which were then recrystallized from a mixture of ethyl acetate and diisopropyl ether to give ethyl 2,3-dihydro-9-methanesulfonyl-1-benzoxepin-4-carboxylate (12.72 g). The mother liquid was concentrated to give additional amount of ethyl 2,3-dihydro-9-methanesulfonyl-1-benzoxepin-4-carboxylate (1.09 g).
mp: 104-105xc2x0 C.
IR (Nujol): 1700, 1640, 1595, 1570, 1300, 1140 cmxe2x88x921 
NMR (CDCl3, xcex4): 1.36 (3H, t, J=7.1 Hz), 3.08 (2H, dt, J=1.2, 4.8 Hz), 3.26 (3H, s), 4.30 (2H, q, J=7.1 Hz), 4.45 (2H, t, J=4.8 Hz), 7.20 (1H, t, J=7.8 Hz), 7.61 (12H, s), 7.63 (1H, dd, J=1.7, 7.8 Hz), 7.96 (1H, dd, J=1.7, 7.8 Hz)
ESI-MS: 297 [M+H]+
Preparation 31
The following compound was obtained according to a similar manner to that of Preparation 26.
Ethyl 2,3-dihydro-9-ethoxycarbonylamino-1-benzoxepin-4-carboxylate
mp: 76.5-78xc2x0 C. (ethyl acetate)
IR (Nujol): 3410, 1729, 1702, 1633 cmxe2x88x921 
NMR (DMSO-d6, xcex4): 1.26 (6H, q, J=7.1 Hz), 2.8-2.95 (2H, m), 4.01-4.39 (6H, m), 7.01 (1H, t, J=7.9 Hz), 7.17 (1H, dd, J=1.6, 7.9 Hz), 7.50 (1H, s), 7.74 (1H, dd, J=1.6, 7.9 Hz), 8.66 (1H, s)
APCI-MS: 306 [M+H]+
Preparation 32
A solution of sodium nitrate (800 mg) in water (3 ml) was added to a suspension of ethyl 9-amino-2,3-dihydro-1-benzoxepin-4-carboxylate (2.56 g) in a mixture of conc. hydrochloric acid (18 ml) and acetic acid (12.5 ml) under sodium chloridexe2x80x94ice bath cooling, and the mixture was stirred at the same temperature for 50 minutes. On the other hand, sulfur dioxide gas was introduced to acetic acid (40 ml) at room temperature, and the solution was cooled to xe2x88x9210xc2x0 C. under stirring. To this was added copper(II) chloride (545 mg), followed by addition of the diazonium salt solution dropwise. After the addition was completed, the mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into ice-water, and extracted with ethyl acetate (xc3x973). The combined extracts were successively washed with water, saturated aqueous sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give ethyl 9-chlorosulfonyl-2,3-dihydro-1-benzoxepin-4-carboxylate (0.72 g) as an oil.
NMR (CDCl3, xcex4): 1.37 (3H, t, J=7.1 Hz), 3.13 (2H, dt, J=1.3, 4.8 Hz), 4.30 (2H, q, J=7.1 Hz), 4.51 (2H, t, J=4.8 Hz), 7.20 (1H, t, J=7.9 Hz), 7.60 (1H, s), 7.71 (1H, dd, J=1.6, 7.8 Hz), 7.94 (1H, dd, J=1.6, 7.8 Hz)
Preparation 33
A solution of ethyl 9-chlorosulfonyl-2,3-dihydro-1-benzoxepin-4-carboxylate (0.50 g) in tetrahydrofuran (12 ml) was cooled in an ice bath. To this solution was added dropwise morphorine (0.69 ml) at 5xc2x0 C. The reaction mixture was stirred at 5xc2x0 C. for 40 minutes and partitioned between ethyl acetate and water. The aqueous layer was extracted twice with ethyl acetate. The combined organic layer was dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel using a mixture of n-hexane and ethyl acetate (1:1) to give ethyl 2,3-dihydro-9-morphorinosulfonyl-1-benzoxepin-4-carboxylate (0.54 g).
mp: 123-124xc2x0 C. (ethyl acetate)
IR (Nujol): 1707, 1639 cmxe2x88x921 
NMR (DMSO-d6, xcex4): 1.28 (3H, t, J=7.1 Hz), 2.85-3.00 (2H, m), 3.05-3.20 (4H, m), 3.55-3.70 (4H, m), 4.22 (2H, q, J=7.1 Hz), 4.30-4.45 (2H, m), 7.23 (1H, t, J=7.8 Hz), 7.58 (1H, s), 7.70-7.95 (2H, m)
APCI-MS: 368 [M+H]+
Preparation 34
The following compounds were obtained according to a similar manner to that of Preparation 33.
(1) Ethyl 9-aminosulfonyl-2,3-dihydro-1-benzoxepin-4-carboxylate
mp: 197-198xc2x0 C. (95% ethanol)
IR (Nujol): 3300, 3230, 1685, 1630, 1565 cmxe2x88x921 
NMR (DMSO-d6, xcex4): 1.29 (3H, t, J=7.1 Hz), 2.94 (2H, t, J=4.6 Hz), 4.22 (2H, q, J=7.1 Hz), 4.39 (2H, t, J=4.6 Hz), 7.18 (1H, t, J=7.7 Hz), 7.24 (2H, s), 7.77 (2H, d, J=7.7 Hz)
(2) Ethyl 2,3-dihydro-9-methylaminosulfonyl-1-benzoxepin-4-carboxylate
mp: 137-139xc2x0 C. (ethyl acetate)
IR (Nujol): 3318, 1705 cmxe2x88x921 
NMR (DMSO-d6, xcex4): 1.28 (3H, t, J=7.1 Hz), 2.44 (3H, d, J=4.5 Hz), 2.90-3.00 (2H, m), 4.22 (2H, q, J=7.1 Hz), 4.35-4.45 (2H, m), 7.21 (1H, t, J=7.7 Hz), 7.58 (1H, s), 7.7-7.9 (2H, m)
APCI-MS: 312 [M+H]+
Preparation 35
A mixture of ethyl 2,3-dihydro-9-iodo-1-benzoxepin-4-carboxylate (1.00 g), trifluoroacetic acid, sodium salt (1.58 g), and copper(I) iodide (1.11 g) in 1-methyl-2-pyrrolidinone (10 ml) was stirred at 160xc2x0 C. under nitrogen atmosphere for 6 hours and partitioned between ethyl acetate and 1N hydrochloric acid. The aqueous layer was extracted twice with ethyl acetate. The combined organic layer was washed successively with saturated aqueous sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel using a mixture of n-hexane and ethyl acetate (4:1) to give ethyl 2,3-dihydro-9-trifluoromethyl-1-benzoxepin-4-carboxylate (0.93 g).
mp: 57-59xc2x0 C. (ethyl acetate)
IR (Nujol): 3334, 3140, 1702, 1652, 1590 cmxe2x88x921 
NMR (DMSO-d6, xcex4): 1.29 (3H, t, J=7.1 Hz), 2.85-3.10 (2H, m), 4.23 (2H, q, J=7.1 Hz), 4.25-4.45 (2H, m), 7.23 (1H, t, J=7.8 Hz), 7.58 (1H, s), 7.66 (1H, d, J=7.8 Hz), 7.84 (1H, d, J=7.8 Hz)
APCI-MS: 287 [M+H]+
Preparation 36
To a mixture of ethyl 9-amino-2,3-dihydro-1-benzoxepin-4-carboxylate (1.0 g) and triethylamine (4.18 ml) in tetrahydrofuran (10 ml) was added dimethylsulfamoyl chloride (2.30 ml) at 5xc2x0 C. The reaction mixture was stirred overnight at ambient temperature and partitioned between ethyl acetate and 1N hydrochloric acid. The organic layer was washed successively with saturated aqueous sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel using a mixture of n-hexane and ethyl acetate (4:1) to give ethyl 2,3-dihydro-9-dimethylsulfamoylamino-1-benzoxepin-4-carboxylate (0.89 g).
mp: 93-96xc2x0 C. (ethyl acetate)
IR (Nujol): 3249, 1711 cmxe2x88x921 
NMR (DMSO-d6, xcex4): 1.27 (3H, t, J=7.1 Hz), 2.67 (3H, s), 2.75 (3H, s), 2.85-3.00 (2H, m), 4.10-4.35 (4H, m), 7.01 (1H, t, J=7.8 Hz), 7.27 (1H, d, J=7.8 Hz), 7.38 (1H, d, J=7.8 Hz), 7.51 (1H, s), 9.11 (1H, s)
APCI-MS: 341 [M+H]+
Preparation 37
The following compound was obtained according to a similar manner to that of Preparation 36.
Ethyl 2,3-dihydro-9-sulfamoylamino-1-benzoxepin-4-carboxylate
mp: 135-137xc2x0 C.
IR (Nujol): 3348, 3261, 1699 cmxe2x88x921 
NMR (DMSO-d6, xcex4): 1.28 (3H, t, J=7.1 Hz), 2.75-3.00 (2H, m), 4.10-4.40 (4H, m), 7.02 (1H, t, J=7.8 Hz), 7.10 (2H, br s), 7.19 (1H, dd, J=7.8, 1.6 Hz), 7.42 (1H, dd, J=7.8, 1.6 Hz), 7.47 (1H, s), 8.32 (1H, s)
APCI-MS: 313 [M+H]+
Preparation 38
A solution of ethyl 9-carboxy-2,3-dihydro-1-benzoxepin-4-carboxylate (1.0 g) in tetrahydrofuran (10 ml) was cooled in an ice bath. To this solution was added 1-hydroxybenzotriazole hydrate (0.57 g) and 1-(3-dimethylaminopropyl)-3-ethylcarboxiimide hydrochloride (0.80 g). Thereto aqueous ammonia (0.28 ml) was added dropwise at 5xc2x0 C. The reaction mixture was stirred for 7 hours at ambient temperature and partitioned between ethyl acetate and 1N hydrochloric acid. The aqueous layer was extracted twice with ethyl acetate. The combined organic layer was washed successively with saturated aqueous sodium bicarbonate and brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel using a mixture of chloroform and methanol (9:1) to give ethyl 2,3-dihydro-9-carbamoyl-1-benzoxepin-4-carboxylate (0.31 g).
mp: 120-125xc2x0 C. (ethyl acetate)
IR (Nujol): 3450, 3176, 1703, 1666 cmxe2x88x921 
NMR (DMSO-d6, xcex4): 1.28 (3H, t, J=7.1 Hz), 2.80-3.05 (2H, m), 4.24 (2H, q, J=7.1 Hz), 4.25-4.45 (2H, m), 7.11 (1H, t, J=7.6 Hz), 7.40-7.90 (5H, m)
APCI-MS: 262 [M+H]+